This proposal describes novel methodology for the synthesis of several hydropyran-containing natural products of potential therapeutic value: dihydrocompactin (a hypocholesterolemic agent) and he spiroketal units of the milbemycin/avermectin family of antibiotics (antiparasitic agents). The compactin synthesis features substrate-controlled reactions on a macrocyclic lactone for establishing the desired configurations at remote stereocenters. Two dihydroxy decanolides to be prepared in this study are likely to be pro-drugs of a structural type not yet reported. The hydronapthalene portion of the target molecule is to be prepared via a modification of a new tandem Michael-aldol reaction sequence recently developed in this laboratory. The milbemycin-avermectin portion of the proposal study uses reagent-controlled reactions (Sharpless epoxidation and asymmetric hydroboration) to establish remote stereogenic centers while an aromatic ring serves as a latent beta-dicarbonyl unit. Extension of this strategy to the synthesis of tetra- and higher polyketides, structural subunits of many important biomolecules, will be examined.